The compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha.-globulin, angiotensinogen, to procude angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure.
K. Matsumura, et al., in U.S. Pat. No. 4,207,324 issued June 10, 1980 discloses 1, 2-disubstituted-4-haloimidazole-5-acetic acid derivatives of the formula: ##STR2## wherein R.sup.1 is hydrogen, nitro or amino; R.sup.2 is phenyl, furyl or thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R.sup.3 is hydrogen or lower alkyl and X is halogen; and their physiologiclly acceptable salts. These compounds have diuretic and hypotensive actions.
Furukawa, et al., in U.S. Pat. No. 4,355,040 issued Oct. 19, 1982 discloses hypotensive imidazole-5-acetic acid derivatives having the formula: ##STR3## wherein R.sup.1 is lower alkyl, cycloalkyl, or phenyl optionally substituted; X.sup.1, X.sup.2, and X.sup.3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y is halogen and R.sup.2 is hydrogen or lower alkyl; and salts thereof.
Furukawa, et al., in U.S. Pat. No. 4,340,598, issued July 20, 1982, discloses hypotensive imidazole derivatives of the formula: ##STR4## wherein R.sup.1 is lower alkyl or, phenyl C.sub.1-2 alkyl optionally substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl or phenyl optionally substituted; one of R.sup.3 and R.sup.4 is --(CH.sub.2).sub.n COR.sup.5 where R.sup.5 is amino, lower alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R.sup.3 and R.sup.4 is hydrogen or halogen; provided that R.sup.1 is lower alkyl or phenethyl when R.sup.3 is hydrogen, n=1 and R.sup.5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa et al., in European patent application No. 103,647 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula: ##STR5## where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid is disclosed by H. Torii in Takeda Kenkyushoho, 41, No. 3/4, 180-191 (1982).
Copending U.S. patent application Ser. No. 884,920 filed July 11, 1986, now abandoned, discloses antihypertensive imidazoles of the formula. ##STR6## R.sup.2, R.sup.3 and R.sup.4 are each independently H; Cl; Br; I; F; NO.sub.2 ; alkyl of 1 to 4 carbon atoms; alkoxy of 1 to 4 atoms; CO.sub.2 H; CO.sub.2 R.sup.9 ; NHSO.sub.2 R.sup.10 ; CONHOR.sup.11 ; NHCOR.sup.12 ; NHNO.sub.2 ; SO.sub.2 NHR.sup.11 ; ##STR7## aryl; or furyl; R.sup.5 is H; alkyl of 1 to 6 carbon atoms; allyl benzyl;
R.sup.6 is alkyl of 3 to 10 carbon atoms, alkenyl or perfluoroalkyl of 3 to 10 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; cycloalkylalkyl, cycloalkylalkenyl of 4 to 10 carbon atoms; ech of the above groups containing 0 or 1 --O--, --S--, --SO--, --SO.sub.2, or --NH-- linkage optionally substituted with 0 or 1 groups selected from F, Cl, Br, I, --OR.sup.11 or --CO.sub.2 R.sup.14 ; phenyl or benzyl optionally substituted with 0 to 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; perfluorophenyl; PA1 R.sup.7 is H, F, Cl, Br, I, NO.sub.2, CF.sub.3 or CN; PA1 R.sup.8 is alkyl of 1 to 10 carbon atoms, containing 0 or 1 --O--, --S--, --SO, --SO.sub.2, or NH; phenyl-alkenyl wherein the aliphatic portion is 2 to 6 carbon atoms, alkenyl of 3 to 10 carbon atoms, ##STR8## CONR.sup.18 R.sup.19, --(CH.sub.2).sub.m -imidazol-1-yl, --(CH.sub.2).sub.m -1, 2, 3-triazoyl optionally substituted with one or two groups selected from CO.sub.2 R.sup.14 or alkyl of 1 to 4 carbon atoms, --(CH.sub.2).sub.m -tetra-zolyl, ##STR9## R.sup.9 is ##STR10## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ; PA1 R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; PA1 R.sup.12 is perhaloalkyl of 1 to 6 carbon atoms; PA1 R.sup.13 is --CO.sub.2 H; --CO.sub.2 R.sup.9 ; ##STR11## --PO.sub.3 H; --C(CF.sub.3).sub.2 OH; --C(CF.sub.3).sub.2 NH.sub.2 ; --NHSO.sub.2 R.sup.10 ; --CONHOR.sup.11 ; --NHCOR.sup.12 ; NHNO.sub.2 ; --SO.sub.2 NHR.sup.11 ; ##STR12## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; PA1 R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; PA1 R.sup.16 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ; PA1 R.sup.17 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or phenyl; PA1 R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, pheny;, benzyl or taken together form a ring of the formula ##STR13## Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl; PA1 R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR14## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6; PA1 R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ; PA1 R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR15## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbonatoms, benzyl, or allyl; PA1 R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; PA1 R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --; PA1 X is a carbon-carbon single bond, --CO--, --O--, --S--, ##STR16## --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28), --NHSO.sub.2 --, --SO.sub.2 NH--, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR17## Y is O or S; m is 1 to 5; PA1 n is 1 to 10; PA1 p is 0 to 3; PA1 q is 1 to 3; PA1 r is 0 to 2; PA1 s is 0 to 5; PA1 t is 0 or 1; PA1 (1) the R.sup.1 group is not in the ortho position and when R.sup.1 is CO.sub.2 H, then it is also not in the meta position; PA1 (2) when R.sup.1 is ##STR18## X is a single bond, and R.sup.13 is CO.sub.2 H, ##STR19## then r.sup.13 must be in the ortho or meta position; or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 R.sup.10, R.sup.13 must be ortho; PA1 (3) when R.sup.1 is ##STR20## and X is other than a single bond, then R.sup.13 must be ortho except when X =NR.sup.17 CO and R.sup.13 is NHSO.sub.2 R.sup.10, then R.sup.13 must be ortho or meta; PA1 (4) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl; PA1 (5) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H; PA1 (6) when R.sup.1 is ##STR21## X is --NR.sup.17 CO, and R.sup.13 is 2-CO.sub.2 H, then R.sup.6 cannot be C.sub.6 H.sub.5 (CH.sub.2).sub.3 ; PA1 (7) when R.sup.1 is ##STR22## X is --CH.sub.2 O--, and R.sup.13 is 2-CO.sub.2 H, then R.sup.6 is not C.sub.2 H.sub.5 S or (C.sub.6 H.sub.5).sub.2 CH(CH.sub.2).sub.2 S. PA1 R.sup.4 is H, or alkyl of 1-4 carbon atoms; PA1 R.sup.5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.6, or NR.sup.7 R.sup.8 ; PA1 R.sup.6 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl; PA1 R.sup.7 and R.sup.8 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together with nitrogen form a ring of the formula ##STR25## Q is NR.sup.9, O, or CH.sub.2 ; R.sup.9 is H, alkyl of 1 to 4 carbon atoms, or phenyl; PA1 R.sup.10 is alkyl of 1 to 6 carbon atoms; PA1 A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C .sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms; ##STR26## B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms; PA1 X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.2 --; PA1 n is 1 to 6; PA1 m is 0 to 3; PA1 p is 0 to 1; PA1 R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3 ; ##STR27## R.sup.2 is hydrogen; PA1 R.sup.3 is alkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms each of which may be optionally substituted with --OR.sup.4 or CO.sub.2 R.sup.4 ; PA1 R.sup.5 is H, alkyl of 1 to 5 carbon atoms, OR.sup.6 or NR.sup.7 R.sup.8 ; PA1 R.sup.6 is H, alkyl of 1 to 5 carbon atoms; PA1 A is halogen, alkoxy of 1 to 6 carbon atoms; ##STR28## B is H; and pharmaceutically acceptable salts thereof. PA1 R.sup.3 is alkyl of 3 to 5 carbon atoms, alkenyl or alkynyl of 3 to 5 carbon atoms each of which may be optionally substituted with OH, OCH.sub.3, CO.sub.2 H or CO.sub.2 CH.sub.3 ; ##STR29## n is 1-2; X is a carbon-carbon single bond; or --NHCO--; and pharmaceutically acceptable salts thereof. PA1 (a) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-hydrozymethylbenzimidazole ( b) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethylbenzimidazole PA1 (c) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-methoxybenzimidazole PA1 (d) 2- (1-Butenyl)-1-[(2'-carboxybiphenyl-4-yl)-methyl]-6-hydroxymethylbenzimidaz ole; PA1 (e) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-chlorobenzimidazole; and pharmaceutically suitable salts thereof.
and pharmaceutically acceptable salts of these compounds;
provided that:
Copending U.S. patent application Ser. No. 050,341 filed May 22, 1987 as a continuation-in-part of U.S. Ser. No. 884,920, and U.S. patent application Ser. No. 07/142,580, filed simultaneously herewith, as a continuation-in-part of U.S. Ser. No. 050,341, also disclose antihypertensive imidazoles. U.S. application Ser. No. 07/141,669 filed simultaneously herewith, discloses antihypertensive, pyrroles, pyrazoles and triazoles.
Pals et al., Circulation Research, 29, 673 (1971) describe that the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possessed agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
To date there are no known non-peptide antagonists of AII which are useful orally or which bind in vitro in the IC.sub.50 ranges we observe, other than the compounds disclosed in U.S. Ser. Nos. 884,920 and 050,341, and in the two applications filed simultaneously herewith which are mentioned above.